The human cell surface protein CD46 is the main measles virus (MV) receptor. We analyzed the CD46 isoforms expressed in the brain of three patients who died with persistent MV infections and in an unaffected brain. Complete CD46 cDNAs were produced and found to code exclusively for CD46 isoforms with cytoplasmic tail 2. Selective expression of tail 2 isoforms was shown in a second control brain by Western blots with antibodies specific for each of the cytoplasmic tails. Binding of purified MV particles and virus-dependent cell fusion were tested after transient expression of brain-derived CD46 proteins in mouse cells. All the brain-derived proteins mediated MV binding and virus-dependent fusion. Isoforms containing both serine/threonine/proline (STP)-rich domains were more active in virus binding, whereas isoforms with only one STP domain were more efficient in mediating fusion.